Cell cycle-gated feedback control mediates desensitization to interferon stimulation
Cell cycle-gated feedback control mediates desensitization to interferon stimulation
Abstract Cells use sophisticated molecular circuits to interpret and respond to extracellular signal factors, such as hormones and cytokines, which are often released in a temporally varying fashion. In this study, we focus on type I interferon (IFN) signaling in human epithelial cells and combine microfluidics, time-lapse microscopy, and computational modeling to investigate how the IFN-responsive regulatory network operates in single cells to process repetitive IFN stimulation. We found that IFN-α pretreatments lead to opposite effects, priming versus desensitization, depending on the input durations. These effects are governed by a regulatory network composed of a fast-acting positive feedback loop and a delayed negative feedback loop, mediated by upregulation of ubiquitin-specific peptidase 18 (USP18). We further revealed that USP18 upregulation can only be initiated at the G1 and early S phases of cell cycle upon the treatment onset, resulting in heterogeneous and delayed induction kinetics in single cells. This cell cycle gating provides a temporal compartmentalization of feedback control processes, enabling duration-dependent desensitization to repetitive stimulations. Moreover, our results, highlighting the importance of IFN dynamics, may suggest time-based strategies for enhancing the effectiveness of IFN pretreatment in clinical applications against viruses, such as SARS-CoV-2.
Wang Wei、Daugherty Matthew D、Zhang Dong-Er、Arimoto Kei-ichiro、Hao Nan、Mudla Anusorn、Rajesh Adarsh、Ryan Andy P、Xu Bingxian、Jiang Yanfei
Department of Chemistry and Biochemistry, University of California San DiegoSection of Molecular Biology, Division of Biological Sciences, University of California San DiegoSection of Molecular Biology, Division of Biological Sciences, University of California San Diego||Department of Pathology, Moores UCSD Cancer Center, University of California San DiegoSection of Molecular Biology, Division of Biological Sciences, University of California San DiegoSection of Molecular Biology, Division of Biological Sciences, University of California San DiegoSection of Molecular Biology, Division of Biological Sciences, University of California San DiegoDepartment of Bioengineering, University of California San DiegoSection of Molecular Biology, Division of Biological Sciences, University of California San DiegoSection of Molecular Biology, Division of Biological Sciences, University of California San DiegoSection of Molecular Biology, Division of Biological Sciences, University of California San Diego
细胞生物学分子生物学基础医学
Wang Wei,Daugherty Matthew D,Zhang Dong-Er,Arimoto Kei-ichiro,Hao Nan,Mudla Anusorn,Rajesh Adarsh,Ryan Andy P,Xu Bingxian,Jiang Yanfei.Cell cycle-gated feedback control mediates desensitization to interferon stimulation[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2020.05.18.103101.点此复制
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